Drugs serve as positive reinforcers to maintain and strengthen behavior leading to their administration and can control behavior through their ability to function as discriminative stimuli. In many situations, drugs of abuse function through pharmacological and behavioral mechanisms to persistently sustain long sequences of drug seeking behavior that are very resistant to extinction. These long sequences of drug-seeking behavior can be analyzed using schedule-controlled performances in the same way as operant behavior maintained by other events such as food or shock. Using a variety of intravenous self-administration procedures in rats and primates, ongoing experiments are being conducted to evaluate behavior maintained by drugs and the ability of pharmacological treatments, (i.e., antagonist administration or the development of dependence) and/or behavioral manipulations to modify drug self-administration behavior and/or food-maintained behavior. These studies will compare responding maintained under fixed-ratio, fixed interval and complex second-order schedules, by various drugs including cocaine, nicotine and other psychomotor stimulants, benzodiazepines and other sedative/anxiolytics, morphine and other opioids and delta-9 THC (the active ingredient of marijuana). For example, since serotonergic mechanisms appear to underlie psychomotor stimulant action, recent studies evaluated the effects of sertraline, a selective serotonergic uptake inhibitor that is effective as an antidepressant, on the reinforcing effects of i.v. nicotine in squirrel monkeys. In addition to differences in the pharmacological efficacy of drugs to control or modify behavior, it is clear that behavioral and environmental factors play an important role in the control that even highly efficacious drugs exert on behavior. The focus of experiments in the rhesus self- administration lab are to study the pharmacological, behavioral, and environmental variables involved in initiating and maintaining drug self- administration. Recent studies assessed rates of acquisition of cocaine self-injection in rhesus monkeys found a relationship with behavioral history, but not activity level. Additional studies are evaluating the effects of serotonergic antagonists on delta-amphetamine self-injection and noradrenergic antagonists and uptake inhibitors on cocaine self- injection. In another study, we are evaluating the reinforcing efficacy of the stereoisomers of l-deprenyl (selegiline) in comparison to methamphetamine and its l-stereoisomer, as well as evaluating the ability of deprenyl pretreatment to alter self-administration of cocaine, methamphetamine or beta-phenylethylamine.